Process of preparing levo-1-phenyl-2-methylamino-propanol-1



Patented Sept. 26, 1933 rRocE s s or PREPARING LEVO-l-PHENYL- Z-METHYLAMINO-PROPANOL-l Friedrich Stolz and Julius Hallensleben, Frankfort-on-the-Main, Germany, assignors toWinthrop Chemical Company, Inc., New York Y.,

a corporation of New York NoDrawing. Application July 10, 1930, Serial No. 467,129, and in Germany August 31, l929 3 Claims. (Cl. 260-1285) The present invention relates'to a process of preparing optically active l-phenyle2emethylamino-propanols-l. a y

We have found-that the therapeutically very [important levo-l-phenyl 2 methylamino pros.

pano1.-l which is identical with the natural ephedrine can easily be obtained in an excellent yield,

by mixingv at a suitable temperature molecular quantities of synthetically prepared base of dex- 10 tro-levo phenylpropanol methylamine in pan ethylsalcoholie solution with dextrotartaric acid. Instead of ethyl-alcohol also other solvents such as propylealcohol etc. and water may be used. Almost all of the dextro-bitartrate of dextro-ll5 phenyl-Z-methylamino-propanol-1 which is more difiicultly soluble in alcohol crystallizes from the ethyl-alcoholic solution, whereas the dextro-bitartrate of levo.-1:phenyl-Z-methylamino -propanol-l remains'in solution. Thelevo-base is 1) separated from the solution in the usual manner and is then separated from admixed racemic base forinstance by dissolving in an acid the levo- 1-pheny1-2 e methylamino propanol 1 obtained from the mother liquor and treating the neutral Z5 solutien with the quantity of ammonium oxalate required for the race nic base. The racemic base s th s eci a in h fo o e Iat while the, levo-l-phenyl-Z-methyl -.aminopropanc rem in in h m r liquor- O ork- 5". 'ing up these mother liquors a strongly rotary levoelrphenyle2-methyl-aminoepropano1-1 is obtained, which, when transformed into the hydro? I chloride and recrystallized, has a rotation of This separation may also be effectedyby treating the optically active l-phenyl-2-methylamino-prow panol-l contaminated by racemic base with or- 40 game or inorganic acids in suitable solvents, for instance by treating the mixture of racemic base and optically active base, suspended in water, with oxalic acid.

Another procedure is to mix with alkali the mix- 45, 'ture of levo-base and racemic base in the form of their salts, the portions first precipitating being more strongly rotary than those precipitated later on. For complete separation, however, this amino-propanol l the specificrotation is alcohol and the solution is allowedtostand-until crystallization occurs. I After 3- 4 day'stthe pref cipitated fdextro-tartrate of dextro l-phenyl gmethylamino-propanol-l is filtered by suction,.

The mother liquors are freed from'alcohol and the remaining tartrate of l-phenyl-Z-methylamino-propanol-l is transformed into its hydrochloride.- There are obtained about 300, grams of phenylpropanol-rnethylamine-hydrochloride with a rotationfof a=0.53; H

As for a 100 per cent. levo-l-phenyl-2-methylcontain 38-39 "per cent. of a 100 percent. lei/0 1 phenyl- 2 methylamino propanol-l'. These 300 grams of the hydrochloride; therefore, contain about 39 per cent. i. e.; 11!? grams of the hydro chloride of the pure levo-base. In order to separate the racemic compound from the 183 grams of the hydrochloride of racemic base calculated on this base to be present,'the racemic compound is dissolved in about 900 cc. of water and warm ammonium oxalate solution of strength gram in a l) is introduced dropby oa, When all th m n um o a e ol tio has been addedythe precipitated 'dextro-levo 1 phenyl-2-methylamino-propanol-1-oxalate is filtered by suction and the levo- -lphenyl-2-methylamino-propanol-l is extracted with ether from I the f mother liquors, after addition of excess of f alkali ,';"and' transformed into the hydrochloride; 1

After recrystallization from alcohol 0196 percent;

strength "the le'vo-I- phenyI-Z-methyIamino propanol l-hydrochloride is obtained having a rota- The hydrochloride melts at 214 C.215 C.

Instead of ammonium oxalate, other oxalates may be used for the precipitation; furthermore the bitartrate of 1-phenyl-2-methylamino-propanol-l, remaining after distillation of the alcohol, may directly be used, dissolved in Water and neutralized, for the precipitation'of dextro.

iii)

levo-1-phenyl-2-methylamino propanol-1 with I aid of an oxalate.

In the following examples the fractions ob tained according to Example '1 by separating with tartaricacid and still contaminated by racemic base, are used as starting-materials.

(2). grams of levo 1 phenyl 2 methylare dissolved in 60 cc. of watern This solution amino-propano'l-l-hydrochloride having an ini-r tial rotation of is rendered alkaline by addition of 100 cc. of normal alkaline lye. Nearly all of the base remains in solution. The whole is then treated by slowly adding, while stirring, 3.2 grams of oxalic acid dissolved in 32 cc. of water. The precipitated oxalate of 1-phenyl-2-methylamino-propanol-l is filtered by suction. It is only feebly levo-rotatory. The levo-base is extracted with ether from the motherliquors and transformedinto the hydrochloride. The hydrochloride obtained is levo-rotatory. When the specific 'rotationis further increased by recrystallization from alcohol of 96 per cent. strength to 7 (3). 15 grams 7 of levo-1-phehyl-2-n1ethylam-- ino-propanol-l having an initial rotation of are dissolved in grams of acetone."

grams of alcoholic hydrochloric acid of about 34% strength are introduced into the solution drop by drop, while stirring. The precipitated levo-l-phenyl-2-1nethylamino-propanol-1 hydrochloride is filtered and well washed with ether.

The rotation of the 1-phenyl-2-methy1aminopropanol-l hydrochloride thus obtained is: a

By recrystallizing from alcohol of 96 per cent strength the rotation is raised to" Q re (4). 15 grams of levo-l-ph'enyl-Z-methylamino-propanol-l of a specific rotation are dissolved in 25 cc. of alcohol and the solution is precipitated. with 2.3 grams of sulfuricacid dissolved in 10 cc. of alcohol. Theprecipitated sulfate is filtered by suction, it is feebly levoride obtained has a higher of an organic acidupon the solution of a salt,

rotatory. The alcohol is distilled off from the mother liquors, the residue is dissolved in ether and transformed into the hydrochloride. The rotation is:

(5). 20 grams of -1evo-1-phenyl-2-methylamino-propanol-l hydrochloride (initial rotation of a 1 17.25"), are dissolved in cc. of water and 2.6 grams of sodiun1.-,carbonate, dissolved in 26 grams of wavter, are introduced drop by drop. The precipitated levo-1 phenyl-Z-methylamino-propyl 1 is extracted with ether and the base dissolved therein precipitated in the form of the hydrochloride with alcoholic hydrochloric acid. The levo-'1-. phenyl 2 -methylamino propanol-l hydrochlorotation than that of the parent material. 7 a

In the following claims the reaction of a salt e. .g. of the hydrochloride, of the impure levo-lphenyl-2-methylamino propanol 1 base is equivalent to the reaction of the organic acidupon the free base in the presence of a solvent. We claim: Y

' 1.' In the manufacture of levo-1-phenyl 2- methylarnino propanol 1' by resolving 'dextro levo 1 phenyl-2-methylamino-propanol 1 by means of dextro-tartaric acid the steps which comprise freeing the impure levo-base, obtained 11 0 as product of the resolution, from admixed racemic base, by precipitating theracemic'base byaddition of the requisite quantityof a soluble salt of oxalic acid to the solution of a salt of the impure base. I I

2. In the manufacture of levo-l-phenyl-Z- methylamino-propanol-l by resolving dextroievo 1 phenyl-Z-methylarnino-propanol -l 'by by means of dextro-tartaric acid' the steps which i v comprise freeing theimpurelevo-base, obtained as products of the resolution, from the admixed racemic base by precipitating'theracemic base f by addition of the requisite quantity of the ammonium salt of oxalic acid to the aqueoussolution of a salt of the impure base.

3.-In the manufacture of levo-l-phenyl-2- methylamino-propanol-l by resolving dextrolevo 'l' phenyl-Z methylamino-propanol 1 by I means of dextro-tartaric acid the steps which comprise freeing the impure levo-base, obtained 130 as product of the resolution, from admixed rac'emic base by precipitating the racemic base by addition of the requisite quantity of the' ammonium salt of oxalic acid to the aqueous solu- 

